returned a positive result. The first MERS disease outbreak

occurred earlier, in Jordan.

Overall, >80% of cases of MERS have occurred in the Kingdom

of Saudi Arabia (KSA) afflicting mostly males older than 45-

years with underlying medical conditions. Clusters of disease in healthcare facilities have coincided

with steep climbs in case numbers during April of 2013 (Al-Ahsa) and 2014 (Jeddah, KSA and Abu

Dhabi in the United Arab Emirates [UAE]). Disease in children is infrequent and seems to be milder.

Approximately a fifth of cases have occurred in healthcare workers.

Only 2 deaths and few cases have

occurred among those under the age

of 20-years. Camels are considered

the most likely animal source for this

zoonotic infection and primary cases

acquired after exposure to camels

seem to be more serious in severity.

Sporadic human-to-human

transmission does occur, but is

inefficient. No sustained

transmission has been reported. So

and is likely responsible for most

cases, but transmission No definitive

animal source has been identified but

bats and camels are suspects for now.

Members of the subfamily Coronavirinae that infect humans currently include the respiratory coronaviruses HCoV-OC43 (a betaCoV), HCoV-229E (alphaCoV), HCoV-NL63 (alphaCoV), SARS-CoV (betaCoV), MERS-CoV and HCoV-HKU1 (both betaCoV).A graph of the accumulating laboratory-confirmed MERS-CoV detections (green mountain, includes fatalities), fatalities (red dots) and the rolling proportion of fatal cases (PFC; black). Please don't go nuts and draw any major conclusions based on extrapolating the PFC to the global population - this figure is solely meant to show you the numbers and trends in this population at this time and these circumstances. It cannot be directly extrapolated. What it does show us is how the outbreak came to be noticed - fatalities - and how with time, the denominator (survivors) is increasing at a greater rate than reported deaths. This chart uses Dates of Onset (DOO) of illness, where available, but is augmented by Dates of Hospitalisation/Reporting (DOH/DOR) for the remainder. While this is inaccurate, it does serve the purpose of generally showing how quickly the cases are accumulating.

The locations of MERS-CoV in humans...

In March and April 2014, a surge of MERS-CoV detections occurred which included a complete clinical range of outcomes from asymptomatic to fatal. It was associated with more MERS-CoV than the tally of all cases that had come before. It was centred in Jeddah and coincided with a smaller healthcare-related outbreak in the UAE. Over 80% of detections of MERS-CoV originate from the KSA.

The MERS-CoV genes and genome...

On 13-Jun-2013, there were 9 complete MERS-CoV genomes, now there are >40. Those from a human cluster such as that in the Al-Ahsa hospital cluster can be seen to group together closely (reflecting their genetic similarity). Keep in in mind that despite the apparently obvious differences in the phylogenetic tree above, all of these genomes share >99% identity (29,935 identical pieces of their genomes with a pairwise identity 99.8%). I have added an arrow to show time advancing, and how the complete genome tree shows that accurately. More detailed analyses of MERS-CoV sequences can be found from Andrew Rambaut, Uni of Edinburgh. I also have a tree of full CoV genome at the VDU CoV page.Some genomes include:•JX869059. Human betacoronavirus 2c EMC/2012•KF192507 Middle East respiratory syndrome coronavirus•KC667074 Human betacoronavirus 2c England-Qatar/2012•KC164505 Betacoronavirus England 1•KC776174 Human betacoronavirus 2c Jordan-N3/2012•KF186567 Middle East respiratory syndrome coronavirus Al-Hasa_1_2013•KF186566 Middle East respiratory syndrome coronavirus Al-Hasa_2_2013•KF186565 Middle East respiratory syndrome coronavirus Al-Hasa_3_2013•KF186564 Middle East respiratory syndrome coronavirus Al-Hasa_4_2013Could another perhaps shorter (subgenomic) genomic region, amplified for speed and for smaller or less genomics-focussed laboratories, encompass the same degree of accuracy as full genomes, allowing us to monitor viral change with time? The Spike gene shows limited differences (99.7% identical nucleotides sequences, as visualized in the alignment picture below) between the 9 complete genomes examined. However, the differences that do exist may be useful for tracking any change in the virus as it passages between people. It already appears that the older virus (that isolated from the Jordan outbreak in in April-2012) differs from the most recent genomes from the Al-Ahsa hospital outbreak, but there is very little difference in the 4 Al-Ahsa genomes

MERS the disease...

The Middle East respiratory syndrome (MERS) is a disease (a change in the body away from normal function towards abnormal function) comprised of a bunch of signs and symptoms (the syndrome bit) that is identified in patients who turn up ("present") to their doctor/clinic/hospital with signs (things the doctor can see or measure e.g. coughing, sneezing or a fever with a temperature about 38°C) and symptoms (things the doctor can't see that may still be measurable or not e.g. lung inflammation upon X-Ray, muscle aches or chills but no measurable fever). At the bad end of the disease spectrum, MERS is an acute community-acquired pneumonia (CAP; confirmed by X-Ray of the lungs) that progresses to be worse. "Worse" includes kidney failure acute respiratory distress syndrome, respiratory failure and multi-organ failure. MERS pneumonia cannot be told apart from acute CAP due to other causes. Laboratory testing to confirm the presence of the agent you suspect, is essential. You can't confirm its absence, but you can say it was "not detected".MERS is a particularly nasty disease for those who already have a disease that is chronic. These include diabetes, kidney disease, heart disease, hypertension, lung disease, obesity, malignancy and those who smoke or use steroids. This appears to more often include older males around the Arabian peninsula in whom the coronavirus that is assumed to cause MERS (MERS-CoV), has had a big impact, associated with the most severe forms of the disease and death. Neonates, infants, toddlers and children (up to 14-years) are in the minority of MERS-CoV detection to date (14 of 361 with age data, or 3.9%).Over 85% of patients with MERS (remember: the disease, not the virus) have a fever >38°C, cough and chills or rigors (shaking episode) and all have an abnormal 1st chest X-Ray. Around half have a runny nose and about a third have malaise (feel rubbish) and myalgia (aching or sore muscles). A quarter have diarrhoea and a fifth have sore throat, nausea or vomiting.18

Early MERS cases...

The first case of MERS, identified retrospectively, was admitted to hospital in April 2012. I define Week 1 in all my MERS-CoV data as that week which begins 19-March since illness for this case began 21-Mar.The first case of MERS to yield a characterised virus admitted to hospital 10th June 2012. He was a previously healthy non-smoker who died after community-acquired pneumonia progressed to acute respiratory distress syndrome (ARDS) and acute respiratory failure (ARF). No contacts were positive.Nasal swabs from 154 French pilgrims collected before and after Hajj-2012 tested negative for MERS-CoV using Corman's assays5, despite 90% suffering from respiratory symptoms during their stay in Saudi Arabia.8A number of human clusters have been reported, for example:A Jordan Cluster: Jordan, 2 cases/2 of whom died: Utilising a WHO collaboration (via a United States Naval Medical Research Unit No. 3 [NAMRU-3] team in Cairo, Egypt), the Jordanian Ministry of Health sent samples from an outbreak of severe pneumonia among mainly healthcare workers during April 2012, for characterization. At the time (24th April, 2012)the samples were negative for normal coronaviruses as this preceded the existence of any MERS-CoV-specific diagnostics. However, 2 deaths from this time were subsequently confirmed as RT-PCR positive to, or had an antibody-conversion against, the MERS-CoV by NAMRU-3 (November, 2012; once tests were in use).11. Patient 1-25M University student, onset 21.03.12, 7d cough, fever, shortness of breath, died 25.04.12; Patient 2-40F intensive care unit nurse, onset 02.04.12, death 19.04.12)11. A mission from the WHO Eastern Mediterranean Regional Office (EMRO) was despatched on the 29th November to assist with surveillance. A complete genome (Human betacoronavirus 2c Jordan-N3/2012) is available from this cluster. 124 samples were sent to the US CDC ion late May 2013 for retrospective analyses.A KSA Cluster: Saudi Arabia, 4 cases/2 deaths: This was a family cluster of four cases and two deaths.12 Patient 1 (70M), showed signs of disease from Oct 5, 2012 was hospitalized Oct 13 and died Oct 23 from cardiogenic and septic shock. He was given steroids. He had type 2 diabetes, ischemic heart disease and hypertension. Patient 2 (39M), eldest son of Patient 1, presented Oct 28 after 4 days of fever, rigors, anorexia and a productive cough requiring continuous positive airway pressure (CPAP) until his oxygen levels normalised and he was discharged. He was re-admitted, this time to intensive care, on Oct 29. He was given oseltamivir Oct 26 but died Nov 2. He was a chronic smoker with a history of airway disease. Patient 3 (16M), eldest son of Patient 2, reported malaise (feeling rotten), fever, sore throat, cough, wheeze and anorexia from Nov 3 and was admitted with a measurable fever, continuing symptoms and diarrhoea and abdominal pain. He was discharged Nov 11. Patient 4 (31M), brother of Patient 1, reported fever, rigors, night sweats and productive cough Nov 4 and was admitted Nov 6 and discharged Nov 14. He was a smoker. All were treated with oseltamivir and antibiotics.A United Kingdom Cluster: United Kingdom, 3 cases/2 deaths: Illness in a 60-year old male (60M) returned from travelling in Pakistan and Saudi Arabia led to his hospitalization during which he tested positive for the MERS-CoV (Feb 1)9. A second, non-travelling adult male with an underlying medical condition, also from the same household died after contracting the virus and becoming ill on Feb 5 after hospital-based contact with the index case. A female became ill Feb 5 after contact with the index case in hospital and recovered, as an outpatient, by Feb 19. This family cluster was classified as person-to-person transmission.A French Cluster: France, 2 cases/1 death: A 64M became symptomatic on 22nd of April, 5-days after returning to France from travelling to Dubai.10 He was hospitalized on the 24th, subsequently required extracorporeal membrane oxygenation (ECMO)and died 28th May due to multiple organ failure. The second case in this cluster was a 51M who became ill while located 1.5m from 64M, in the same hospital room for 3-days (admitted for unrelated reasons). Like other visitors and healthcare workers, he wore no mask. 51M was released from hospital Apr 30 but was admitted to another hospital May 9 with symptoms. His infection was confirmed May 11, he suffered respiratory failure May 12 and remains hospitalised.For an update on the most recent epidemiology, please visit my blog, virologydownunder.blogspot.com.auand use the search box to find recent “MERS” or “camel” posts.

The denominator problem...

You may remember from your early maths classes that fractions have both a numerator (the number on on top or before a slash/line, that represents a portion of the whole) and a denominator (the non-zero number on the bottom or after the line that represents all the parts of the whole). MERS cases were, until perhaps early 2014, identified by people being sick enough to presnt (turn up) to a hospital. Most had pneumonia as confirmed by X-Ray. We did not see many mild or asymptomatic cases (virus positive but no obvious feelings of signs of illness) until perhaps June 2013. This might have been because there were no mild cases or because only the worst cases were laboratory tested and the contacts of them were simply observed to see if they developed disease.Many milder respiratory diseases look the same based on signs and symptoms but can be caused (and I use that word with caution) by many, many different respiratory viruses. Even pneumonia. There may be cases of respiratory infection going around in the KSA that are MERS-CoV-positive but not severe enough to warrant admission to hospital or even a trip to the Doctor. Until we know more about this part of the MERS-CoV story, we won't know the total number of infections that are occurring, so we can't calculate the true denominator.Obviously, if the denominator is small (like it was early on with so few MERS-CoV-laboratory positive cases and those being from mostly severe illness or deaths, then we see a high proportion (percentage) as our Proportion of Fatal Cases (PFC; x severe cases over a small number of total cases is a high proportion). If there are mild cases of MERS-CoV infection out there and they are in large numbers, that denominator could be much larger and the severe disease cases will be "diluted" down to a smaller proportion (x severe cases over a large number of mild and severe total cases is a low proportion).

Animal host and risk...

Bats were the suspected host for the nearest ancestor of the zoonotic spread of MERS-CoV to humans, based on previous findings of genetically related CoVs (found in the Japanese pipistrelle, Pipistrellus BatCoV-HKU5 and the lesser bamboo bat, Tylonycteris BatCoV-HKU47). Most of the ground breaking work in finding CoVs in bats comes from The University of Hong Kong.7Then we learned that a MERS case from Abu Dhabi, UAE had been exposed to a sick camel.In August 2013, a collaborative European publication described antibodies in the sera of dromedary ("Arabian") camels from Oman and Spain that reacted or cross-reacted with a recombinant antigen of the MERS-CoV spike protein. While the paper did not find whole or infections virus or viral RNA, it was a leap forward in understanding that something similar to MERS-CoV, if not the virus itself, could come from contact with these animals. RNA was subsequently found in camels and in 2014 a study suggested an infection had passed from camel to human (providing a “direction” to the transmission process).On 24-April-2014, the WHO updated its risk assessment to recommend people take precautions when visiting premises housing camels, especially those people at risk of severe disease. The WHO19 and the US Centers for Disease Control and Prevention (US CDC)20 have excellent advice and information about risks.

Diagnostics and detection...

The MERS-CoV strain HCoV-EMC can be grown in cell culture using LLC-MK2 and Vero cells.1,2 This method has been used to produce antigen for detection antibodies in humans via immunofluorescence methods.1,2 The HCoV-EMC strain also replicates in fully differentiated human airway bronchial epithelium (HAE) cultures grown at the air-liquid interface (ALI).4The first genetic detection of a MERS-CoV was completed using a conventional (non-real-time) pan-coronavirus RT-PCR.3 More specific real-time RT-PCR (RT-rtPCR) assays were described subsequently.5

Immune response...

Human bronchial epithelial airway (HAE) cultures were used to compare and contrast MERS-CoV to SARS-CoV and HCoV-229E.4 [this will be added shortly]

Therapies and interventions...

There is no specific drug or vaccine currently available to treat or prevent infection by the MERS-CoV. Care is supportive. But some research advances in this area include:Drug testing of US FDA-approved potential formulations is under way at the Small-molecule Inhibitor Leads Versus Emerging and neglected RNA viruses (SILVER) project. The company Novavax has produced an experimental recombinant nanoparticle vaccine candidate based on the Spike protein that generated important anti-MERS-CoV antibodies in a mouse model.14,17 Monolconal antibnodies (e.g. MERS-4, MERS-27 and 3B11) capable of neutralizing infection by the MERS-CoV also hold promise for future use as a therapeutic and prophylactic.15,16

Middle East respiratory syndrome coronavirus (MERS-CoV)

Last Updated 03-May-2014

Written by Ian M. Mackay, PhD on his personal time.All opinions are his own and do not represent medical advice or the views of any other institution. Data are from public sources.Graphics are compiled for general interest. Please use freely, citing this website and me.

Structure of an coronavirus virion. Use images freely but please cite www.virologydownunder.blogspot.com.au and Dr. Ian M Mackay as their source. Click on image to enlarge.

Enveloped, roughly spherical, 120-160nm, large club like protrusion (spike protein)

Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gammacoronavirus

Timeline of some key events in the MERS story, 2012-2013. Use images freely but please cite www.virologydownunder.blogspot.com.au and Dr. Ian M Mackay as their source. Click on image to enlarge.

A schematic of the complete genome of the first fully sequenced MERS-CoV variant in lineage C of the betacoronaviruses, HCoV 2c EMC/2012.1Drawn to scale based on GenBank sequence JX869059. This genome shares 99% nucleotide identity with two other fully sequence variants, Human betacoronavirus 2c England-Qatar/2012 (KC667074) and Human betacoronavirus 2c Jordan-N3/2012 (KC7761745) complete genomes. Use images freely but please cite www.virologydownunder.blogspot.com.au and Dr. Ian M Mackay as their source. Click on image to enlarge.